ペンタミジン 化学特性,用途語,生産方法
効能
抗真菌薬, 抗原虫薬
説明
Pentamidine is an aromatic diamine that is effective against protozoal diseases, such as amoebic dysentery, malaria, trypanosomiasis, and leishmaniasis. In clinical studies, it has also been shown to be an effective prophylaxis against pneumocystis pneumonia.
化学的特性
Crystalline Solid
適応症
Pentamidine (Pentam 300) binds to DNA and may inhibit
kinetoplast DNA replication and function. It also
may act by inhibiting dihydrofolate reductase and interfering
with polyamine metabolism. An effect on organism
respiration, especially at high doses, also may play a
role.
抗菌性
Pentamidine has broad activity in experimental models against
P. falciparum, Toxoplasma gondii, Leishmania spp., Trypanosoma
spp. and Babesia spp. It also has activity against Pn. jirovecii.
獲得抵抗性
Relapse rates of 7–16% have been reported in the treatment
of human African trypanosomiasis in West Africa. Patients
usually respond to a subsequent course of treatment with
melarsoprol. A membrane transporter is involved in crossresistance
of arsenic-resistant T. brucei to diamidines, affecting
diminazene and stilbamidine more than pentamidine.
応用例（製薬）
A synthetic diamidine, available as the isethionate
(2-hydroxymethane sulfonate) salt for parenteral use. It is also
administered by instillation of a nebulized solution directly
into the lungs.
作用機序
Pentamidine is not well absorbed from the intestinal
tract after oral administration and generally is given by
intramuscular injection. The drug binds to tissues, particularly
the kidney, and is slowly excreted, mostly as the
unmodified drug. It does not enter the central nervous
system (CNS). Its sequestration in tissues accounts for
its prophylactic use in trypanosomiasis.
薬物動態学
Oral absorption: Negligible
C
max 4 mg/kg intramuscular: c. 0.5 mg/L after 1 h
Plasma half-life: c. 6.5 h
Volume of distribution: 3 L/kg
Plasma protein binding: c. 70%
Pentamidine is rapidly and extensively metabolized by rat liver,
and high concentrations are retained in renal and hepatic tissue
for up to 6 months after administration. In humans distribution
is mainly in the liver, kidney, adrenal glands and spleen,
with lower accumulation in the lung. This tissue retention is
the basis for its prophylactic use. Although transport across
the blood–brain barrier has been demonstrated in experimental
models, it is probably unable to cross the blood–brain
barrier in sufficient quantity to be trypanocidal: <1% of the
plasma concentration has been measured in the CSF of sleeping
sickness patients. About 15–20% of the dose is excreted
in the urine but because of retention in tissues there is an
extremely long terminal half-life (>12 days).
臨床応用
Pentamidine is active against Pneumocystis carinii,
trypanosomes, and leishmaniasis unresponsive to pentavalent
antimonials. It is an alternative agent for the
treatment of P. carinii pneumonia. Although it is more
toxic than trimethoprim–sulfamethoxazole, it has been
widely used in patients with acquired immunodeficiency
syndrome (AIDS), in whom P. carinii infection is
common.
Pentamidine is an alternative drug for visceral leishmaniasis,
especially when sodium stibogluconate has
failed or is contraindicated. Pentamidine is also a reserve
agent for the treatment of trypanosomiasis before
the CNS is invaded. This characteristic largely restricts
its use to Gambian trypanosomiasis.
副作用
Side effects range from local irritation and sterile abscess at
the site of injection to transient effects (vomiting, abdominal
discomfort) and serious systemic effects (hypotension, effects
on the heart, hypoglycemia and hyperglycemia, leukopenia,
thrombocytopenia). In a study of the treatment of South
American cutaneous leishmaniasis, 17% of patients prematurely
terminated treatment due to toxicity and another 30%
reported side effects.
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